C-9 alkenylidine bridged macrolides

ABSTRACT

The present invention discloses compounds of formulae (I), (II) or pharmaceutically acceptable salts, esters, or prodrugs thereof: 
                         
which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes process by which to make the compounds of the present invention.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/859,440, filed on Nov. 16, 2006. The entire teachings of the aboveapplication are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel semisynthetic macrolides havingantibacterial activity that are useful in the treatment and preventionof bacterial infections. More particularly, the invention relates to C9alkyl and C9 alkylidenyl compounds with bridging at C6-C11 or C3-C6,compositions containing such compounds and methods for using the same,as well as processes for making such compounds.

BACKGROUND OF THE INVENTION

The spectrum of activity of macrolides, including erythromycin, coversmost relevant bacterial species responsible for upper and lowerrespiratory tract infections. 14-membered ring macrolides are well knownfor their overall efficacy, safety and lack of serious side effects.Erythromycin however is quickly degraded into inactive products in theacidic medium of the stomach resulting in low bioavailability andgastrointestinal side effects. Improvement of erythromycinpharmacokinetics has been achieved through the synthesis of moreacid-stable derivatives, for example, roxithromycin, clarithromycin, andthe 15-membered ring macrolide azithromycin. However, all of thesedrugs, including 16-membered ring macrolides, present several drawbacks.They are inactive against MLS_(B)-resistant streptococci(MLS_(B)=Macrolides-Lincosamides-type B Streptogramines) and with theexception of azithromycin, weakly active against Haemophilus influenzae.Furthermore, the resistance of Streptococcus pneumoniae to erythromycinhas increased significantly in recent years (5% to above 40%). There isa high percentage of cross-resistance to penicillin among theseisolates, with a worldwide epidemic spread of 10-40% in some areas.

There is, therefore, a clear need for new macrolides that overcome theproblem of pneumococcal resistance, have good pharmacokinetic propertiesand acid stability while continuing to be active against H. influenzae.These new macrolides will be ideal candidates for drug development inthe first line therapy of upper respiratory tract infections (“URTI”)and lower respiratory tract infections (“LRTI”).

Kashimura et al. have disclosed 6-O-methylerythromycin derivativeshaving a tricyclic basic nuclear structure in European Application559896, published Nov. 11, 1991. Also, Asaka et al. have disclosed5-O-desoaminylerythronolide derivatives containing a tricyclic carbamatestructure in PCT Application WO 93/21200, published Apr. 22, 1992.

Erythromycin derivatives containing a variety of substituents at the 6-Oposition have been disclosed in U.S. Pat. Nos. 5,866,549 and 6,075,011as well as PCT Application WO 00/78773. Furthermore, Ma et al. havedescribed erythromycin derivatives with aryl groups tethered to the C-6position in J. Med. Chem., 44, pp 4137-4156 (2001). PCT application WO97/10251, published Mar. 20, 1997, discloses intermediates useful forpreparation of 6-O-methyl 3-descladinose erythromycin derivatives. U.S.Pat. Nos. 5,866,549 and 6,075,011, and PCT application WO 00/78773,published Dec. 28, 2000, disclose certain 6-O-substituted erythromycinderivatives.

PCT Application WO 03/095466 A1, published Nov. 20, 2003 and PCTApplication WO 03/097659 A1, published Nov. 27, 2003 disclose a seriesof 6-11 bicyclic erythromycin derivatives. Recent U.S publication nos.2006/0122128, 2006/0142214, 2006/0142215, and 2006/0148731 disclose aseries of 3,6 bicyclolide derivatives.

PCT Application WO2006/047167, published May 4, 2006 discloses 9 alkyland 9-alkylidenyl 6-0 alkyl-11,12-carbamate ketolide derivatives.

SUMMARY OF THE INVENTION

The present invention provides a novel class of C3-C6 bridgederythromycin compounds that possess antibacterial activity.

The compounds of the present invention are represented by formulae (I)and (II) as illustrated below:

or the racemates, enantiomers, diastereomers, geometric isomers,tautomers, solvates, pharmaceutically acceptable salts, esters andprodrugs thereof, wherein T is:

-   -   (a) —R₁—, where R₁ is substituted or unsubstituted —C₁-C₈        alkylene-, —C₂-C₈ alkenylene- or —C₂-C₈ alkynylene-, containing        0, 1, 2, or 3 heteroatoms selected from O, S or N;    -   (b) —R₁—(C═O)—R₂—, where R₂ is independently selected from R₁;    -   (c) —R₁—(C═N-E-R₃)—R₂—, where E is absent, 0, OC(O), NH, NHC(O),        NHC(O)NH or NHSO₂; and R₃ is independently selected from the        group consisting of:        -   (1) hydrogen;        -   (2) aryl; substituted aryl; heteroaryl; substituted            heteroaryl; and        -   (3) R₄, where R₄ is substituted or unsubstituted —C₁-C₈            alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl containing 0, 1, 2,            or 3 heteroatoms selected from O, S or N; and        -   (4) substituted or unsubstituted, saturated or unsaturated            C₃-C₁₂ cycloalkyl;    -   (d) —R₁—[C(OR₅)(OR₆)]—R₂—, where R₅ and R₆ are selected from the        group consisting of C₁-C₁₂ alkyl, aryl or substituted aryl; or        taken together is —(CRxRy)_(m)-, where m is 2 or 3, Rx and Ry        are independently selected from hydrogen and R₄;    -   (e) —R₁-[C(SR₅)(SR₆)]—R₂—; or    -   (f) —R₁—(C═CH—R₃)—R₂—;        one of A and B is R_(a) and the other is OR_(a), wherein R_(a)        is independently selected from:    -   (a) hydrogen; and    -   (b) —R₄.        Alternatively, A and B taken together with the carbon atom to        which they are attached to form ═CHCH(R_(b))X₁ or        ═CHM₁C(R_(b))═N—OR_(c), wherein R_(b) is selected from the group        consisting of:    -   (a) hydrogen;    -   (b) —R₃;    -   (c) —C(O)—R_(d), wherein R_(d) is independently selected from        halogen and R₃;    -   (d) —C(O)—O—R_(d); and    -   (e) —C(O)—NR₈R₉ wherein R₈ and R₉ are each independently        selected R₃; alternatively, R₈ and R₉ taken together with the        nitrogen atom to which they are connected form a 3- to        7-membered ring which may optionally contain one or more        heterofunctions selected from the group consisting of: —O—,        —NH—, —N(R₄)—, —N(R₁₀)—, —S(O)_(n)—, wherein n=0, 1 or 2, and        R₁₀ is selected from aryl; substituted aryl; heteroaryl; and        substituted heteroaryl;        Rc is selected from the group consisting of:    -   (a) hydrogen;    -   (b) —R₄;    -   (c) —R₁₀;    -   (d) —(CO)R₃;    -   (e) —(CO)NHR₃;    -   (f) —(CO)OR₃;    -   (g) —C(O)—NR₈R₉; and    -   (h) —C(O)—NR₁₁NR₁₂R₁₃; wherein R₁₁ is hydrogen or alkyl, and R₁₂        and R₁₃ are independently selected from R₄;        X₁ is selected from the group consisting of:    -   (a) hydrogen;    -   (b) oxo;    -   (c) azido;    -   (d) cyano;    -   (e) —R₄;    -   (f) —R₁₀;    -   (g) —(CO)R₃;    -   (h) —(CO)NHR₃;    -   (i) —(CO)OR₃;    -   (j)—C(O)—NR₈R₉;    -   (k) —OR₁₄, where R₁₄ is selected from the group consisting of        N-phthalimido and Rc;    -   (l) —SR₃;    -   (m)—NR₉R₉; and    -   (n) —NR₃R₁₄;        M₁ is absent or R₁;        L is independently selected from R₄;        W is selected from:    -   (a) hydrogen;    -   (b) —R₄;    -   (c) —C(O)R₃;    -   (d) —C(O)O—R₃; and    -   (e) —C(O)N(R₈R₉);        Q is:    -   (a) —R₃;    -   (b) —(CO)R₃;    -   (c) —(CO)NHR₃;    -   (d) —(CO)OR₃;    -   (e) —(SO)₂R₃;    -   (f) monosaccharide;    -   (g) disaccharide; or    -   (h) trisaccharide;        Z is:    -   (a) hydrogen;    -   (b) —N₃;    -   (c) —CN;    -   (d) —NO₂;    -   (e) —CONH₂;    -   (f) —COOH;    -   (g) —CHO;    -   (h) —R₄;    -   (i) —COOR₄;    -   (j)—C(O)R₄; or    -   (k) —C(O)NR₈R₉;        when U is hydrogen, V is selected from the group consisting of:    -   (a) hydrogen;    -   (b) —OR₃;    -   (c) —OC(O)R₃;    -   (d) —OC(O)NHR₃;    -   (e) —OS(O)₂R₃;    -   (f) —O-monosaccharide; and    -   (g) —O-disaccharide.        Alternatively, U and V taken together with is oxo.        Each of X and Y is independently:

a) hydrogen;

b) hydroxy;

c) halogen; or

d)—R₄;

G is selected from the group consisting of:

-   -   a) hydrogen;    -   b) hydroxy;    -   c) —O—R₄;    -   d) —O—R₁₀.        Alternatively, G and W taken together to a form cyclic structure        selected from:

where M is O or N-J-R₂₀, and where J is absent, O, NH, NH(CO), or N═CH;and R₂₀ is selected from the group consisting of:

-   -   i. hydrogen;    -   ii. R₄; and    -   iii. R₁₀.

In another embodiment of the present invention there are disclosedpharmaceutical compositions comprising a therapeutically effectiveamount of a compound of the invention in combination with apharmaceutically acceptable carrier or excipient. In yet anotherembodiment of the invention are methods of treating antibacterialinfections in a subject in need of such treatment with saidpharmaceutical compositions. Suitable carriers and formulations of thecompounds of the present invention are disclosed.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment of the compounds of the present invention arecompounds represented by formulae I and II as illustrated above, or apharmaceutically acceptable salt, ester or prodrug thereof.

In a second embodiment of the compounds of the present invention arecompounds represented by formula III as illustrated below, or apharmaceutically acceptable salt thereof:

where X₂ is C(O) or CH₂; Y₂ is absent, O, S, NH, CO, (CO)O, (CO)NH, SO,SO₂, CS, (CS)NH, O(CO)O, O(CO)NH, O(CO), (CO)O, NH(CO)O, NH(CO),NH(CO)NH, NH(SO₂), SO₂NH, NH(SO₂)NH, or C═N—E—R₃; Z₂ is hydrogen, R₄ orR₁₀; R_(p) is hydrogen, hydroxy protecting group, ester or hydroxyprodrug; Y and T is as previously defined.

In a third embodiment of the compounds of the present invention arecompounds represented by formula IV as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

where X₂, Y₂, Z₂, Y and R_(p) are as previously defined.

In a fourth embodiment of the compounds of the present invention arecompounds represented by formula V as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

where X₂, Y₂, Z₂, Y and R_(p) are as previously defined.

In a fifth embodiment of the compounds of the present invention arecompounds represented by formula VI as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

where X₂, Y₂, Z₂, T, R₂₀ and R_(p) are as previously defined.

In a sixth embodiment of the compounds of the present invention arecompounds represented by formula VII as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

where X₂, Y₂, Z₂, R₂₀ and R_(p) are as previously defined.

In an seventh embodiment of the compounds of the present invention arecompounds represented by formula VIII as illustrated below, or apharmaceutically acceptable salt, ester or prodrug thereof:

where X₂, Y₂, Z₂, R₂₀ and R_(p) are as previously defined.

Representative compounds according to the invention are those selectedfrom the group consisting of:

Compounds (1)-(173) of the formula A:

wherein Z₂ is delineated for each example in Table 1.

TABLE 1 Compound No. —Z₂ (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

(48)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

(62)

(63)

(64)

(65)

(66)

(67)

(68)

(69)

(70)

(71)

(72)

(73)

(74)

(75)

(76)

(77)

(78)

(79)

(80)

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(86)

(87)

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(90)

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(92)

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(94)

(95)

(96)

(97)

(98)

(99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

(107)

(108)

(109)

(110)

(111)

(112)

(113)

(114)

(115)

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(117)

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(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

Further representative species of the present invention are:Compounds (174)-(346) of the formula B:

wherein Z₂ is delineated for each example in Table 2.

TABLE 2 Compound No. —Z₂ (174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

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(335)

(336)

(337)

(338)

(339)

(340)

(341)

(342)

(343)

(344)

(345)

(346)

Further representative species of the present invention are:Compounds (347)-(370) of the formula C:

wherein Y₂, Z₂, T, and R_(p) are delineated for each example in Table 3.

TABLE 3 Compound No. T Y₂ Z₂ R_(p) (347) —CH₂(C═CH₂)CH₂— —O(C═O)NHNH—

Ac (348) —CH₂(C═CH₂)CH₂— —O(C═O)NHNH—

H (349) —CH₂(C═O)CH₂— —O(C═O)NHNH—

H (350) —CH₂(C═CH₂)CH₂— —NH—

H (351) —CH₂(C═CH₂)CH₂— —NH—

Ac (352) —CH₂(C═CH₂)CH₂— —NH—

H (353) —CH₂(C═CH₂)CH₂— —NH—

Ac (354) —CH₂(C═CH₂)CH₂— —NH—

H (355) —CH₂(C═CH₂)CH₂— —NH—

Ac (356) —CH₂(C═CH₂)CH₂— —NH—

H (357) —CH₂CH═CHCH₂— —NH—

H (358) —CH₂(C═CH₂)CH₂— —NH—

Ac (359) —CH₂(C═CH₂)CH₂— —NH—

H (360) —CH₂(C═CH₂)CH₂— —NH—

H (361) —CH₂(C═CH₂)CH₂— —NH—

H (362) —CH₂(C═CH₂)CH₂— —NH(C═O)NH—

Ac (363) —CH₂(C═CH₂)CH₂— —NH(C═O)NH—

H (364) —CH₂(C═CH₂)CH₂— —NH(C═O)NH—

H (365) —CH₂(C═CH₂)CH₂— —NH(C═O)O—

H (366) —CH₂(C═CH₂)CH₂— —NH(C═O)NH—

Ac (367) —CH₂(C═CH₂)CH₂— —NH(C═O)NH—

H (368) —CH₂CH═CHCH₂— —NH(C═O)NH—

H (369) —CH₂CH═CHCH₂— —NH—

H (370) —CH₂CH═CHCH₂— —NH—

H

A further embodiment of the present invention includes pharmaceuticalcompositions comprising any single compound delineated herein, or apharmaceutically acceptable salt, ester, or prodrug thereof, with apharmaceutically acceptable carrier or excipient.

Yet another embodiment of the present invention is a pharmaceuticalcomposition comprising a combination of two or more compounds delineatedherein, or a pharmaceutically acceptable salt, ester, or prodrugthereof, with a pharmaceutically acceptable carrier or excipient.

Yet a further embodiment of the present invention is a pharmaceuticalcomposition comprising any single compound delineated herein incombination with one or more antibiotics known in the art, or apharmaceutically acceptable salt, ester, or prodrug thereof, with apharmaceutically acceptable carrier or excipient.

In addition, the present invention contemplates processes of making anycompound delineated herein via any synthetic method delineated herein.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyland the like.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclic(e.g. bi-, or tri-cyclic or more) aromatic radical or ring having fromfive to ten ring atoms of which one or more ring atom is selected from,for example, S, O and N; zero, one or two ring atoms are additionalheteroatoms independently selected from, for example, S, O and N; andthe remaining ring atoms are carbon, wherein any N or S contained withinthe ring may be optionally oxidized. Heteroaryl includes, but is notlimited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzooxazolyl, quinoxalinyl, and the like.

In accordance with the invention, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

The terms “C₁-C₆ alkyl,” or “C₁-C₁₂ alkyl,” as used herein, refer tosaturated, straight- or branched-chain hydrocarbon radicals containingbetween one and six, or one and twelve carbon atoms, respectively.Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl andn-hexyl radicals; and examples of C₁-C₁₂ alkyl radicals include, but arenot limited to, ethyl, propyl, isopropyl, n-hexyl, octyl, decyl, dodecylradicals.

The term “C₂-C₆ alkenyl,” as used herein, denotes a monovalent groupderived from a hydrocarbon moiety containing from two to six carbonatoms having at least one carbon-carbon double bond by the removal of asingle hydrogen atom. Alkenyl groups include, but are not limited to,for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and thelike.

The term “C₂-C₆ alkynyl,” as used herein, denotes a monovalent groupderived from a hydrocarbon moiety containing from two to six carbonatoms having at least one carbon-carbon triple bond by the removal of asingle hydrogen atom. Representative alkenyl groups include, but are notlimited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like.

The term “C₃-C₁₂-cycloalkyl,” as used herein, denotes a monovalent groupderived from a monocyclic or polycyclic saturated carbocyclic ringcompound by the removal of a single hydrogen atom. Examples include, butnot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo [2.2.1]heptyl, and bicyclo [2.2.2]octyl.

It is understood that any alkyl, alkenyl, alkynyl and cycloalkyl moietydescribed herein can also be an aliphatic group, an alicyclic group or aheterocyclic group. An “aliphatic group” is non-aromatic moiety that maycontain any combination of carbon atoms, hydrogen atoms, halogen atoms,oxygen, nitrogen or other atoms, and optionally contain one or moreunits of unsaturation, e.g., double and/or triple bonds. An aliphaticgroup may be straight chained, branched or cyclic and preferablycontains between about 1 and about 24 carbon atoms, more typicallybetween about 1 and about 12 carbon atoms. In addition to aliphatichydrocarbon groups, aliphatic groups include, for example,polyalkoxyalkyls, such as polyalkylene glycols, polyamines, andpolyimines, for example. Such aliphatic groups may be furthersubstituted.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or bicyclic saturated carbocyclic ring compound by theremoval of a single hydrogen atom. Examples include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may befurther substituted.

The term “heterocyclic” as used herein, refers to a non-aromatic 5-, 6-or 7-membered ring or a bi- or tri-cyclic group fused system, where (i)each ring contains between one and three heteroatoms independentlyselected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds,(iii) the nitrogen and sulfur heteroatoms may optionally be oxidized,(iv) the nitrogen heteroatom may optionally be quaternized, (iv) any ofthe above rings may be fused to a benzene ring, and (v) the remainingring atoms are carbon atoms which may be optionally oxo-substituted.Representative heterocycloalkyl groups include, but are not limited to,[1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl,pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may befurther substituted.

The terms “substituted aryl’, “substituted heteroaryl,” “substitutedC₁-C₆ alkyl,” “substituted C₁-C₁₂ alkyl,” “substituted C₂-C₆ alkenyl,”“substituted C₂-C₆ alkynyl,” “substituted C₁-C₈ alkylene,” “substitutedC₂-C₈ alkenylene,” “substituted C₂-C₈ alkynylene,” “substitutedaliphatic,”, or “substituted C₃-C₁₂ cycloalkyl,” as used herein, referto aryl, heteroaryl, C₁-C₆ alkyl, C₁-C₁₂ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₈ alkylene, C₂-C₈ alkenylene, aliphatic, or C₃-C₁₂cycloalkyl groups as previously defined, substituted by independentreplacement of one, two, or three or more of the hydrogen atoms thereonwith substituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxyl, —NO₂, —CN, —NH₂, protected amino, —NH—C₁-C₁₂-alkyl,—NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl,—NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino,-diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl,—O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl,—O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl,—C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH— aryl, —OCONH— heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂— aryl, —NHCO₂—heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂, —NHC(O)NH—C₁-C₁₂-alkyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl,—NHC(O)NH-heterocycloalkyl, NHC(S)NH₂, —NHC(S)NH—C₁-C₁₂-alkyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl,—NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂, —NHC(NH)NH—C₁-C₁₂-alkyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl,—NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C₁-C₁₂-alkyl,—NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH— aryl, —SO₂NH— heteroaryl, —SO₂NH— heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkyls,and the like can be further substituted.

The term “monosaccharide” embraces radicals of cladinose, allose,altrose, arabinose, erythrose, erythrulose, fructose, D-fucitol,L-fucitol, fucosamine, fucose, galactosamine, D-galactosaminitol,galactose, glucosamine, glucosaminitol, glucose, glyceraldehyde,glycerol, glycerone, gulose, idose, lyxose, mannosamine, annose,psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose,ribose, ribulose, sorbose, tagatose, tartaric acid, threose, xylose andxylulose. The monosaccharide may further be a deoxy sugar (alcoholichydroxy group replaced by hydrogen), amino sugar (alcoholic hydroxygroup replaced by amino group), a thio sugar (alcoholic hydroxy groupreplaced by thiol, or C═O replaced by C═S, or a ring oxygen of cyclicform replaced by sulfur), a seleno sugar, a telluro sugar, an aza sugar(ring carbon replaced by nitrogen), an imino sugar (ring oxygen replacedby nitrogen), a phosphano sugar (ring oxygen replaced with phosphorus),a phospha sugar (ring carbon replaced with phosphorus), a C-substitutedmonosaccharide (hydrogen at a non-terminal carbon atom replaced withcarbon), an unsaturated monosaccharide, an alditol (carbonyl groupreplaced with CHOH group), aldonic acid (aldehydic group replaced bycarboxy group), a ketoaldonic acid, a uronic acid, an aldaric acid, andso forth. Amino sugars include amino monosaccharides, preferablygalactosamine, glucosamine, mannosamine, fucosamine, quinovosamine,neuraminic acid, muramic acid, lactosediamine, acosamine, bacillosamine,daunosamine, desosamine, forosamine, garosamine, kanosamine,kansosamine, mycaminose, mycosamine, perosamine, pneumosamine,purpurosamine, rhodosamine. It is understood that the monosaccharide andthe like can be further substituted.

The terms “disaccharide”, “trisaccharide” and “polysaccharide” embraceradicals of abequose, amicetose, amylose, apiose, arcanose, ascarylose,ascorbic acid, boivinose, cellobiose, cellotriose, chacotriose,chalcose, colitose, cymarose, 2-deoxyribose, 2-deoxyglucose, diginose,digitalose, digitoxose, evalose, evemitrose, gentianose, gentiobiose,hamamelose, inulin, isolevoglucosenone, isomaltose, isomaltotriose,isopanose, kojibiose, lactose, lactosamine, lactosediamine,laminarabiose, levoglucosan, levoglucosenone, β-maltose, manninotriose,melezitose, melibiose, muramic acid, mycarose, mycinose, neuraminicacid, nigerose, nojirimycin, noviose, oleandrose, panose, paratose,planteose, primeverose, raffinose, rhodinose, rutinose, sarmentose,sedoheptulose, sedoheptulosan, solatriose, sophorose, stachyose,streptose, sucrose, α,α-trehalose, trehalosamine, turanose, tyvelose,umbelliferose and the like. Further, it is understood that the“disaccharide”, “trisaccharide” and “polysaccharide” and the like can befurther substituted. Disaccharide also includes amino sugars and theirderivatives, particularly, a mycaminose derivatized at the C-4′ positionor a 4 deoxy-3-amino-glucose derivatized at the C-6′ position.

The term “trisaccharide” includes amino sugars and halo sugars, wherehalo sugars is saccharide group having at least one halogen substituent.

The term “halogen,” as used herein, refers to an atom selected fromfluorine, chlorine, bromine and iodine.

The term “hydroxy activating group”, as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxyl groupso that it will depart during synthetic procedures such as in asubstitution or an elimination reaction. Examples of hydroxyl activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxy”, as used herein, refers to a hydroxy groupactivated with a hydroxyl activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxyl protecting groups for the present invention areacetyl (Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl(TMS or —Si(CH₃)₃).

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group”, as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the artare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of amino protecting groups include, but are not limitedto, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, andthe like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al, Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protogenic organic solvent,” or “protic solvent’ as usedherein, refers to a solvent that tends to provide protons, such as analcohol, for example, methanol, ethanol, propanol, isopropanol, butanol,t-butanol, and the like. Such solvents are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of protogenic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. Tautomers may be incyclic or acyclic. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration unless the text so states; thus acarbon-carbon double bond or carbon-heteroatom double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable include,but are not limited to, nontoxic acid addition salts are salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of the invention. Various forms of prodrugs are known in theart, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

This invention also encompasses pharmaceutical compositions containing,and methods of treating bacterial infections through administering,pharmaceutically acceptable prodrugs of compounds of the invention. Forexample, compounds of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the invention. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

As used herein, unless otherwise indicated, the term “bacterialinfection(s)” or “protozoa infections”; includes, but is not limited to,bacterial infections and protozoa infections that occur in mammals, fishand birds as well as disorders related to bacterial infections andprotozoa infections that may be treated or prevented by administeringantibiotics such as the compounds of the present invention. Suchbacterial infections and protozoa infections and disorders related tosuch infections include, but are not limited to, the following:pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, cysticfibrosis and mastoiditis related to infection by Streptococcuspneumoniae, Haemophilus influenzae, Moraxella catarrhalis,Staphylococcus aureus, Peptostreptococcus spp, or Pseudomonas spp.;pharynigitis, rheumatic fever, and glomerulonephritis related toinfection by Streptococcus pyogenes, Groups C and G streptococci,Clostridium diptheriae, or Actinobacillus haemolyticum; respiratorytract infections related to infection by Mycoplasma pneumoniae,Legionella pneumophila, Streptococcus pneumoniae, Haemophilusinfluenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissueinfections, abscesses and osteomyelitis, and puerperal fever related toinfection by Staphylococcus aureus, coagulase-positive staphylococci(i.e., S. epidermidis, S. hemolyticus, etc.), S. pyogenes, S.agalactiae, Streptococcal groups C-F (minute-colony streptococci),viridans streptococci, Corynebacterium spp., Clostridium spp., orBartonella henselae; uncomplicated acute urinary tract infectionsrelated to infection by S. saprophyticus or Enterococcus spp.;urethritis and cervicitis; and sexually transmitted diseases related toinfection by Chlamydia trachomatis, Haemophilus ducreyi, Treponemapallidum, Ureaplasma urealyticum, or Nesseria gonorrheae; toxin diseasesrelated to infection by S. aureus (food poisoning and Toxic shocksyndrome), or Groups A, S, and C streptococci; ulcers related toinfection by Helicobacter pylori; systemic febrile syndromes related toinfection by Borrelia recurrentis; Lyme disease related to infection byBorrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitisrelated to infection by C. trachomatis, N. gonorrhoeae, S. aureus, S.pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminatedMycobacterium avium complex (MAC) disease related to infection byMycobacterium avium, or Mycobacterium intracellulare; gastroenteritisrelated to infection by Campylobacter jejuni; intestinal protozoarelated to infection by Cryptosporidium spp. odontogenic infectionrelated to infection by viridans streptococci; persistent cough relatedto infection by Bordetella pertussis; gas gangrene related to infectionby Clostridium perfringens or Bacteroides spp.; Skin infection by S.aureus, Propionibacterium acne; atherosclerosis related to infection byHelicobacter pylori or Chlamydia pneumoniae; or the like.

Bacterial infections and protozoa infections and disorders related tosuch infections that may be treated or prevented in animals include, butare not limited to, the following: bovine respiratory disease related toinfection by P. haemolytica., P. multocida, Mycoplasma bovis, orBordetella spp.; cow enteric disease related to infection by E. coli orprotozoa (i.e., coccidia, cryptosporidia, etc.), dairy cow mastitisrelated to infection by S. aureus, S. uberis, S. agalactiae, S.dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.;swine respiratory disease related to infection by A. pleuropneumoniae,P. multocida, or Mycoplasma spp.; swine enteric disease related toinfection by E. coli, Lawsonia intracellularis, Salmonella spp., orSerpulina hyodyisinteriae; cow footrot related to infection byFusobacterium spp.; cow metritis related to infection by E. coli; cowhairy warts related to Infection by Fusobacterium necrophorum orBacteroides nodosus; cow pink-eye related to infection by Moraxellabovis, cow premature abortion related to infection by protozoa (i.e.neosporium); urinary tract infection in dogs and cats related toinfection by E. coli; skin and soft tissue infections in dogs and catsrelated to infection by S. epidermidis, S. intermedius, coagulase neg.Staphylococcus or P. multocida; and dental or mouth infections in dogsand oats related to infection by Alcaligenes spp., Bacteroides spp.,Clostridium spp., Enterobacter spp., Eubacterium spp.,Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp.,Actinomyces spp., Erysipelothrix spp., Rhodococcus spp., Trypanosomaspp., Plasmodium spp., Babesia spp., Toxoplasma spp., Pneumocystis spp.,Leishmania spp., and Trichomonas spp. or Prevotella spp. Other bacterialinfections and protozoa infections and disorders related to suchinfections that may be treated or prevented in accord with the method ofthe present invention are referred to in J. P. Sanford et al., “TheSanford Guide To Antimicrobial Therapy,” 26th Edition, (AntimicrobialTherapy, Inc., 1996).

Antibacterial Activity

Susceptibility tests can be used to quantitatively measure the in vitroactivity of an antimicrobial agent against a given bacterial isolate.Compounds are tested for in vitro antibacterial activity by amicro-dilution method. Minimal Inhibitory Concentration (MIC) isdetermined in 96 well microtiter plates utilizing the appropriate brothmedium for the observed bacterial isolates. Antimicrobial agents areserially diluted (2-fold) in DMSO to produce a concentration range fromabout 64 μg/ml to about 0.03 μg/ml. The diluted compounds (2 μl/well)are then transferred into sterile, uninoculated medium (0.2 mL) by useof a 96 fixed tip-pipetting station. The inoculum for each bacterialstrain is standardized to approximately 5×10⁵ CFU/mL by opticalcomparison to a 0.5 McFarland turbidity standard. The plates areinoculated with 10 μl/well of adjusted bacterial inoculum. The 96 wellplates are covered and incubated at 35+/−2° C. for 24 hours in ambientair environment. Following incubation, plate wells are visually examinedby Optical Density measurement for the presence of growth (turbidity).The lowest concentration of an antimicrobial agent at which no visiblegrowth occurs is defined as the MIC. The compounds of the inventiongenerally demonstrated an MIC in the range from about 64 μg/ml to about0.03 μg/ml.

All in vitro testing follows the guidelines described in the ApprovedStandards M7-A7 protocol, published by the Clinical Laboratory StandardsInstitute (CLSI).

The invention further provides compositions and methods of treatingpatients suffering from an inflammatory condition comprisingadministering to a patient in need thereof, a therapeutically effectiveamount of at least one compound of the invention. Specific examples ofinflammatory conditions treatable according to the invention include,but are not limited to, scleritis; epi-scleritis; allergicconjunctivitis; pulmonary inflammatory diseases, particularly cysticfibrosis (CF), asthma, chronic obstructive pulmonary disease (COPD),allergic bronchopulmonary aspergillosis (ABPA), and sarcoidosis;procto-sigmoiditis; allergic rhinitis; arthritis; tendonitis; apthousstomatitis; and inflammatory bowel disease.

The invention further provides compositions and methods for i)prophylactic treatment of those patients susceptible to the symptoms CFincluding pulmonary infection and inflammation associated with CF, ii)treatment at the initial onset of symptoms of pulmonary infection andinflammation associated with CF, and iii) treatment of ongoing orrelapsing symptoms of infection and inflammation associated with CF. Inaccordance with the invention a compound according to any one ofcompounds of the invention, is administered to a patient in need oftreatment for CF, in amount sufficient to prevent, diminish or eradicatesymptoms of CF including chronic pulmonary inflammation and infection.

Pharmaceutical Compositions.

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al, and WO 98/43,650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

According to the methods of treatment of the present invention,bacterial infections, cystic fibrosis and inflammatory conditions aretreated or prevented in a patient such as a human or another animal byadministering to the patient a therapeutically effective amount of acompound of the invention, in such amounts and for such time as isnecessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the formulae described herein can, for example, beadministered by injection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically excipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the formulae described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The pharmaceutical compositions of this invention can be administeredorally to fish by blending said pharmaceutical compositions into fishfeed or said pharmaceutical compositions may be dissolved in water inwhich infected fish are placed, a method commonly referred to as amedicated bath. The dosage for the treatment of fish differs dependingupon the purpose of administration (prevention or cure of disease) andtype of administration, size and extent of infection of the fish to betreated. Generally, a dosage of 5-1000 mg, preferably 20-100 mg, per kgof body weight of fish may be administered per day, either at one timeor divided into several times. It will be recognized that theabove-specified dosage is only a general range which may be reduced orincreased depending upon the age, body weight, condition of disease,etc. of the fish.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one of ordinary skill in theart. All publications, patents, published patent applications, and otherreferences mentioned herein are hereby incorporated by reference intheir entirety.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are:

-   -   Ac for acetyl;    -   AcOH for acetic acid;    -   AIBN for azobisisobutyronitrile;    -   Boc₂O for di-tert-butyl-dicarbonate;    -   Boc for t-butoxycarbonyl;    -   Bpoc for 1-methyl-1-(4-biphenylyl)ethyl carbonyl;    -   Bz for benzoyl;    -   Bn for benzyl;    -   BocNHOH for tert-butyl N-hydroxycarbamate;    -   t-BuOK for potassium tert-butoxide;    -   Bu₃SnH for tributyltin hydride;    -   BOP for (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium        Hexafluorophosphate;    -   Brine for sodium chloride solution in water;    -   CDI for carbonyldiimidazole;    -   CH₂Cl₂ for dichloromethane;    -   CH₃ for methyl;    -   CH₃CN for acetonitrile;    -   Cs₂CO₃ for cesium carbonate;    -   CuCl for copper (I) chloride;    -   CuI for copper (I) iodide;    -   dba for dibenzylidene acetone;    -   dppb for diphenylphosphino butane;    -   DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;    -   DCC for N,N′-dicyclohexylcarbodiimide;    -   DEAD for diethylazodicarboxylate;    -   DIAD for diisopropyl azodicarboxylate;    -   DIPEA or (i-Pr)₂EtN for N,N,-diisopropylethyl amine;    -   Dess-Martin periodinane for        1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one;    -   DMAP for 4-dimethylaminopyridine;    -   DME for 1,2-dimethoxyethane;    -   DMF for N,N-dimethylformamide;    -   DMSO for dimethyl sulfoxide;    -   DPPA for diphenylphosphoryl azide;    -   EDC for N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide;    -   EDC HCl for N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide        hydrochloride;    -   EtOAc for ethyl acetate;    -   EtOH for ethanol;    -   Et₂O for diethyl ether;    -   HATU for        O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium        Hexafluorophosphate;    -   HCl for hydrogen chloride;    -   HOBT for 1-hydroxybenzotriazole;    -   K₂CO₃ for potassium carbonate;    -   MeOH for methanol;    -   Mg for magnesium;    -   MOM for methoxymethyl;    -   Ms for mesyl or —SO₂—CH₃;    -   Ms₂O for methanesulfonic anhydride or mesyl-anhydride;    -   NaN(TMS)₂ for sodium bis(trimethylsilyl)amide;    -   NaCl for sodium chloride;    -   NaH for sodium hydride;    -   NaHCO₃ for sodium bicarbonate or sodium hydrogen carbonate;    -   Na₂CO₃ sodium carbonate;    -   NaOH for sodium hydroxide;    -   Na₂SO₄ for sodium sulfate;    -   NaHSO₃ for sodium bisulfite or sodium hydrogen sulfite;    -   Na₂S₂O₃ for sodium thiosulfate;    -   NH₂NH₂ for hydrazine;    -   NH₄HCO₃ for ammonium bicarbonate;    -   NH₄Cl for ammonium chloride;    -   NMMO for N-methylmorpholine N-oxide;    -   NaIO₄ for sodium periodate;    -   Ni for nickel;    -   OH for hydroxyl;    -   OsO₄ for osmium tetroxide;    -   TEA or Et₃N for triethylamine;    -   TFA trifluoroacetic acid;    -   THF for tetrahydrofuran;    -   TPP or PPh₃ for triphenylphosphine;    -   Troc for 2,2,2-trichloroethyl carbonyl;    -   Ts for tosyl or —SO₂—C₆H₄CH₃;    -   Ts₂O for tolylsulfonic anhydride or tosyl-anhydride;    -   TsOH for p-tolylsulfonic acid;    -   Pd for palladium;    -   Ph for phenyl;    -   POPd for dihydrogen        dichlorobis(di-tert-butylphosphinito-□P)palladate(II);    -   Pd₂(dba)₃ for tris(dibenzylideneacetone) dipalladium (0);    -   Pd(PPh₃)₄ for tetrakis(triphenylphosphine)palladium (0);    -   PdCl₂(Ph₃P)₂ for trans-dichlorobis(triphenylphosphine)palladium        (II);    -   Pt for platinum;    -   Rh for rhodium;    -   Ru for ruthenium;    -   TBS for tert-butyl dimethylsilyl; or    -   TMS for trimethylsilyl;    -   TMSCl for trimethylsilyl chloride.        Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared.

A process of the invention, as illustrated in Scheme 1, involvespreparing a compound of formula (1-5) by reacting a compound of formula(1-3) with a suitable alkylating agent.

In accordance with Scheme 1, the 9-keto group of erythromycins can beinitially converted into an oxime by methods described in U.S. Pat. No.4,990,602, followed by removal of the cladinose moiety of the macrolideof formula (1-1) either by mild acid hydrolysis or by enzymatichydrolysis to afford compounds of formula (1-2). Representative acidsinclude, but are not limited to, dilute hydrochloric acid, sulfuricacid, perchloric acid, chloroacetic acid, dichloroacetic acid ortrifluoroacetic acid. Suitable solvents for the reaction include, butare not limited to, methanol, ethanol, isopropanol, butanol, water andmixtures there of. Reaction times are typically 0.5 to 24 hours. Thereaction temperature is preferably 0-80° C.

The 2′-hydroxyl and the oxime groups (where R₆₀ is acyl group) areprotected by reaction with suitable hydroxyl protecting reagents.Typical hydroxyl protecting reagents include, but are not limited to,acetylating agents, silylating agents, acid anhydrides, and the like. Amore thorough discussion of solvents and conditions for protecting thehydroxyl group can be found in T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) ed., John Wiley & Son,Inc, 1999. Acetylation of the hydroxyl group is typically accomplishedby treating the compound (1-2) with an acetylating reagent such asacetic anhydride to give compound of formula (10-3).

The erythromycin derivative of formula (1-3) is then reacted with analkylating agent of the formula:

wherein R₃ is as previously defined and R₅₀ is —C₁-C₁₂ alkyl, —C₁-C₁₂alkenyl, or —C₁-C₁₂ alkynyl optionally substituted with one or moresubstitutents selected from halogen, aryl, substituted aryl, heteroaryl,or substituted heteroaryl; —C₃-C₁₂ cycloalkyl.

Most palladium (0) catalysts are expected to work in this process. Somepalladium (II) catalysts, such as palladium (II) acetate, which isconverted into a palladium (0) species in-situ by the actions of aphosphine, will work as well. See, for example, Beller et al. Angew.Chem. Int. Ed. Engl., 1995, 34 (17), 1848. The palladium catalyst can beselected from, but not limited to, palladium (II) acetate,tetrakis(triphenylphospine)palladium (0),tris(dibenzylideneacetone)dipalladium,tetradibenzylideneacetone)dipalladium and the like. Palladium on carbonand palladium (II) halide catalysts are less preferred than otherpalladium catalysts for this process.

Suitable phosphines include, but are not limited to, triphenylphosphine,bis(diphenylphosphino)methane, bis(diphenylphosphino)ethane,bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane,bis(diphenylphosphino)pentane, and tri-o-tolyl-phosphine, and the like.The reaction is carried out in an aprotic solvent, preferably atelevated temperature, preferably at or above 50° C. Suitable aproticsolvents include, but are not limited to, tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone,toluene, hexamethylphosphoric triamide, 1,2-dimethoxyethane,methyl-tert-butyl ether, heptane, acetonitrile, isopropyl acetate andethyl acetate.

Generally, the alkylating agents have the formula (1-4) as previouslydescribed. The preferred alkylating agents are those wherein R₅₀ istert-butyl, isopropyl or isobutyl. The alkylating reagents are preparedby reaction of a diol with a wide variety of compounds for incorporatingthe di-carbonate moiety. The compounds include, but are not limited to,tert-butyl chloroformate, di-tert-butyl dicarbonate, and1-(tert-butoxycarbonyl)imidazole and the reaction is carried out in thepresence of an organic or an inorganic base. The temperature of thereaction varies from about −30° C. to approximately 30° C.

An alternative method of converting the alcohol into the carbonateinvolves treating the alcohol with phosgene or triphosgene to preparethe chloroformate derivative of the diol. The di-chloroformatederivative is then converted into the di-carbonate by the methodsdescribed in Cotarca, L., Delogu, P., Nardelli, A., Sunijic, V,Synthesis, 1996, 553. The reaction can be carried out in a variety oforganic solvents such as dichloromethane, toluene, diethyl ether, ethylacetate and chloroform in the presence of a base. Examples of suitablebases include, but are not limited to, sodium hydroxide, potassiumhydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate,ammonium carbonate, DMAP, pyridine, triethylamine and the like. Thetemperature can vary from 0° C. to approximately 60° C. The reactionruns to completion in 3 to 5 hours.

Scheme 2 outlined the synthesis of intermediate (2-3). Selectivedeprotection of the oxime is typically accomplished via alkalinehydrolysis in protic solvents. Representative alkali include lithiumhydroxide, sodium hydroxide, potassium hydroxide, and the like. Solventswhich are applicable include but are not limited to tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, isopropanol, ethanol, butanol, waterand mixtures thereof. The reaction temperature is preferably 0° to 35°C. and reaction time is preferably 0.5 to 24 hours.

In a like fashion, simultaneous deprotection of both the oxime and the2′ hydroxyl can be accomplished under a variety of conditions.Conditions for deprotection include, but are not limited to, treatingwith an alcoholic solvent at from room temperature to reflux, ortreatment with a primary amine, such as butylamine. Alcoholic solventspreferred for the deprotection are methanol and ethanol. A more thoroughdiscussion of the procedures, reagents and conditions for removingprotecting groups is described in the literature, for example, by T. W.Greene and P. G. M. Wuts In “Protective Groups in Organic Synthesis”3^(rd) ed., John Wiley & Son, Inc, 1999, referred to above herein.

Deoxygenation of compounds of formula (10-1) under reducing conditionsgives the resulting imine followed by hydrolysis by aqueous alcohol atelevated temperature to give compounds of formula (10-2). Many reducingagents can be used to effect this transformation including, but are notlimited to: lithium aluminum hydride, titanium trichloride, sodiumnitrite, sodium thiosulfate, sodium cyanoborohydride, borane, andvarious sulfides such as sodium hydrogen sulfide, sodium ethoxide. For amore detailed account of oxime reduction see J. March In “AdvancedOrganic Chemistry” 4^(th) ed., Wiley & Son, Inc, 1992, which isincorporated by reference herein.

A particularly useful method for the reduction of oximes to thecorresponding imine uses a sulfite reducing agent, such as sodiumnitrite, sodium hydrogensulfite or titanium trichloride under acidicconditions, typically in protic solvents. Representative acids include,but are not limited to, acetic acid, formic acid, dilute hydrochloricacid, dilute phosphoric acid, dilute sulfuric acid, and the like. Proticsolvents include, but are not limited to, mixtures of water andmethanol, ethanol, isopropanol, or butanol. The reaction is typicallycarried out at 25° to 110° C., preferably for between 1 and 10 hours.

Cyclic carbamates (2-3) can be prepared stepwise or via a one-potprocedure. Metallation and a subsequent reaction with CDI provide1-imidazolocarbonyl derivative, which is reacted with ammonia in asuitable solvent such as dimethylformamide, tetrahydrofuran,acetonitrile or the like at room temperature to slightly elevatedtemperature in the presence of base such as NaHMDS, NaH, or the like.

Scheme 3 describes the preparation of intermediate (3-3). Alkylation ofketone (2-3) is readily achieved by treating the said ketone withlithium trimethylsilylacetylide in a solvent such as THF, diethyl etheror dioxane at a temperature ranging from −78° C. to 25° C. for 0.5 to 72hours followed by acidic workup to afford the silyl intermediate (3-1).Deprotection of the alkynyl group of compound (3-1) can be accomplishedby treatment with potassium carbonate in methanol. Selectivereprotection of the 2′-OH can be achieved with acetic anhydride in thepresence of a tertiary amine base, such as pyridine, triethylamine, ordiisopropylethylamine in a suitable solvent such as methylene chloride,chloroform, or THF at temperature ranging from −20° C. to 37° C. for2-72 hours to afford (3-2). The deprotected alkyne can be further usedin a coupling reaction under transition metal mediated conditions (suchas the Sonogashira reaction) to afford substituted compounds of formula(3-3).

Scheme 4 depicts the synthesis of compounds of formula (4-3). Alkyne(3-3) can be reduced to the corresponding alkene (4-1) by catalytichydrogenation over transition metal catalyst such as palladium oncarbon, or Lindlar's catalyst in the presence of hydrogen in analcoholic solvent. Intermediate (4-1) is then treated with a suitablesolvent such as THF, DMF, DMSO for 0.1-2 hours at a temperature rangingfrom −20° C. to 65° C. The reaction mixture is treated with CDI for0.1-2 hours at a temperature ranging from 0° C. to 65° C. to afford thetetracyclic intermediate (4-2). Both intermediates (4-1) and (4-2) canundergo an acid-catalyzed rearrangement reaction in the presence of anappropriate nucleophile to yield the corresponding substitutedpropylidene derivative (4-3). Group X₁, the nucleophilic species in thereaction depicted in Scheme 4, can be, but not limited to, alkyl,alkenyl, O—R₁₄, NR₈R₉, NR₃R₁₄, SR₃, azido. It will be recognized by oneskilled in the art that in the conversion of (4-1) or (4-2) to (4-3)will result in a new stereocenter and potential geometrical isomers, andconsequently (4-3) may exist as a mixture of diastereomers. Thesestereoisomers may be separated at this stage by a suitablechromatographic method, such as silica gel column chromatography orHPLC, or the mixture of stereoisomers may be carried on through thesynthetic sequence, and optionally separated at a later step.

Scheme 5 illustrates the Lewis Acid promoted rearrangement of (4-2) tocompounds of formulae I and II, wherein A and B taken together with thecarbon atom to which they are attached to form ═CHCH(R_(b))X₁, X₁ isOR₁₄ (5-5), SR₃ (5-1), NR₈R₉ (5-3), hydrogen (5-4), azido (5-2).

Scheme 6 shows the preparation of compounds of formula (6-4). Thehydroxy group of intermediate (6-1) can be derivatized by treatment witha base such as sodium hydride, potassium tert-butoxide or triethylamine,and carbonyldiimidazole (CDI) in a suitable solvent such as methylenechloride, chloroform, or THF at a temperature ranging from −20° C. to37° C. for 1-24 hours to yield the acylimidazolide (6-2). The acylimidazolide (6-2) is treated with an appropriately substituted aminefollowed by 2′ deprotection as described above to afford carbamate(6-4).

Scheme 7 depicts an alternate synthesis of carbamate (7-3). Treatment of(6-1) with trichloroacetylisocyanate in an inert solvent, such asmethylene chloride, chloroform, or THF at a temperature ranging from−20° C. to 37° C. for from 1-24 hours to yields theN-trichloroacetylcarbamate (7-1). The N-trichloroacetylcarbamatefunctionality can be hydrolyzed to the corresponding carbamate (7-2) bytreatment with a suitable base, such as 10% sodium hydroxide, in abiphasic solvent system, such as ethyl acetate/water, methylenechloride/water, and the like for 1-24 hours at a temperature rangingfrom 20° C. to 80° C. Alternative bases may likewise be used to effectthis conversion, such as potassium hydroxide, sodium carbonate,potassium carbonate, or a tertiary amine base, such as triethylamine, inan aqueous solvent mixture. Reductive alkylation of primary carbamate(7-2) with a suitably substituted aldehyde in the presence oftrifluoroacetic acid and triethylsilane affords the secondary carbamate(7-3).

Scheme 8 depicts the synthesis amino and urea compounds of formulae(8-4) and (8-5) respectively. The hydroxy group of (6-1) may be oxidizedby treatment with DMSO (dimethylsulfoxide) and a carbodiimide, such asEDCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), in the presence ofpyridinium trifluoroacetate in a suitable solvent, such as methylenechloride, for 1 to 24 hours at a temperature ranging from −20° C. to 37°C. Alternative methods of oxidation include N-chlorosuccinimide anddimethylsulfide complex followed by treatment with a tertiary aminebase, Dess-Martin periodinane, or oxalyl chloride/DMSO followed bytreatment with a tertiary amine base. Reaction of carbonyl compound(8-1) with benzylcarbamate in the presence of a suitable reducing agent,such as triethylsilane, and a suitable acid, such as trifluoroaceticacid provides carbamate (8-2). Carbamate (8-2) can be converted to amine(8-3) by treatment with hydrogen gas in the presence of a transitionmetal catalyst such as palladium on carbon, platinum on carbon, orrhodium in an acidic medium. Amine (8-3) can be transformed to (8-4) bytreatment with an appropriate substituted aldehyde in the presence of asuitable reducing agent, such as sodium cyanoborohydride in the presenceof catalytic acid followed by removal of the 2′-acetyl protecting groupas described above. Alternatively, amine (8-3) can converted to urea(8-5) by treatment with an appropriate substituted isocyanate.

Scheme 9 illustrates another process of the invention by which toprepare compound of the present invention. Conversion of alkenes (2-1)into ketones (2-2) can be accomplished by ozonolysis followed bydecomposition of the ozonide with the appropriate reducing agents. Thereaction is typically carried out in an inert solvent such as, but notlimited to, methanol, ethanol, ethyl acetate, glacial acetic acid,chloroform, methylene chloride or hexane or mixtures thereof, preferablymethanol, preferably at −78° C. to −20° C. Representative reducingagents are, for example, triphenylphosphine, trimethylphosphite,thiourea, and dimethyl sulfide, preferably triphenylphosphine. A morethorough discussion of ozonolysis and conditions therefor may be foundIn J. March, Advanced Organic Chemistry, 4^(th) ed., Wiley & Son, Inc,1992. Alternatively, compounds of formula (9-1) can be prepared fromcompounds of formula (9-2) dihydroxydation with OsO₄ followed by NaIO₄cleavage.

Compounds according to the invention of the formula (9-2) can be furtherfunctionalized in a variety of ways. Scheme 10 details a procedure forthe conversion of the ketone of formula (9-2) into an oxime of formula(10-1). Oxime formation can be accomplished using the appropriatesubstituted hydroxylamine under either acidic or basic conditions in avariety of solvents. Representative acids include, but are not limitedto, hydrochloric, phosphoric, sulfuric, p-toluenesulfonic, andpyridinium p-toluene sulfonate. Likewise, representative bases include,but are not limited to, triethylamine, pyridine, diisopropylethyl amine,2,6-lutidine, and the like. Appropriate solvents include, but are notlimited to, methanol, ethanol, water, tetrahydrofuran,1,2-dimethoxyethane, and ethyl acetate. Preferably the reaction iscarried out in ethanol using triethylamine as the base. The reactiontemperature is generally 25° C. and reaction time is 1 to 12 hours.

It will be appreciated by one skilled in the art that ketones of formula(9-2) can be transformed into alkenes of formula (10-2) and (10-7) viaWittig reaction with the appropriate phosphonium salt in the presence ofa base, see (a) Burke, Tetrahedron Lett., 1987, 4143-4146, (b) Rathkeand Nowak, J. Org. Chem., 1985, 2624-2626, (c) Maryanoff and Reitz,Chem. Rev., 1989, 863-927. Furthermore, vinyl halides of formula (10-7)can be functionalized by Sonogashira coupling with alkynes in thepresence of a palladium catalyst, a copper halide and an amine base togive compounds of formula (10-8) (see (a) Sonogashira, ComprehensiveOrganic Synthesis, Volume 3, Chapters 2, 4; (b) Sonogashira, Synthesis1977, 777.). In a similar manner, alkenes of formula (10-2) can beobtained from vinyl halides (10-7) via Suzuki cross coupling withorganoboron reagents in the presence of a palladium catalyst and a base,or via Stille cross coupling with organostananes in the presence of apalladium catalyst (see (a) Suzuki, J. Organomet. Chem. 1999, 576,147-168, (b) Stille, Angew. Chem. Int. Ed. Engl., 1986, 508-524 (c)Farina, J. Am. Chem. Soc., 1991, 9585-9595).

Furthermore, alcohols of type (10-3) can be prepared by reduction of thecorresponding ketone of formula (10-2) under a variety of conditions(see Hudlicky, M. Reductions in Organic Chemistry, Ellis HorwoodLimited: Chichester, 1984). The alcohols thus derived can be furthermodified to give compounds of formula (10-4). A process to generatecompounds of formula (10-4) includes, but is not limited to, alkylationof the alcohol with an electrophile or conversion of the alcohol into aleaving group, such as a triflate, tosylate, phosphonate, halide, or thelike, followed by displacement with a heteroatom nucleophile (e.g. anamine, alkoxide, sulfide or the like).

Yet another means by which to functionalize ketones of formula (10-2) isvia addition of Grignard reagents to form alcohols of formula (10-5).The requisite Grignard reagents are readily available via the reactionof a variety of alkyl or aryl halides with magnesium under standardconditions (see B. S. Fumiss, A. J. Hannaford, P. W. G. Smith, A. R.Tatchell, Vogel's Textbook of Practical Organic Chemistry, 5 th ed.,Longman, 1989). The addition is performed in an inert solvent, generallyat low temperatures. Suitable solvents include, but are not limited to,tetrahydrofuran, diethylether, 1,4-dioxane, 1,2-dimethoxyethane, andhexanes. Preferably the solvent is tetrahydrofuran or diethylether.Preferably the reaction is run at −78° C. to 0° C.

In a similar way, reaction with other organometallic reagents gives riseto alcohols of formula (10-5). Examples of useful organometallicreagents include, but are not limited to, organo-aluminum,organo-lithium, organo-cerium, organo-zinc, organo-thallium, andorgano-boron reagents. A more thorough discussion of organometallicreagents can be found in B. S. Furniss, A. J. Hannaford, P. W. G. Smith,A. R. Tatchell, Vogel's Textbook of Practical Organic Chemistry, 5 thed., Longman, 1989.

Ketone of formula (9-2) can be further utilized by conversion into amineof formula (10-6) via a reductive amination. Reductive amination isachieved by treating the ketone with an amine in the presence of areducing agent to obtain the product amine (10-6). The reaction can becarried out either with or without added acid. Examples of acids thatare commonly used include, but are not limited to, hydrochloric,phosphoric, sulfuric, acetic, and the like. Reducing agents that effectreductive amination include, but are not limited to, hydrogen and acatalyst, zinc and hydrochloric acid, sodium cyanoborohydride, sodiumborohydride, iron pentacarbonyl, and alcoholic potassium hydroxide.Generally alcoholic solvents are used. The preferred conditions usesodium cyanoborohydride in methanol with added acetic acid.

It will be appreciated by one skilled in the art, that the unsaturatedcompounds represented by compounds (10-2) and (10-8) can be reduced toform the corresponding saturated compound (see Hudlicky, M., Reductionsin Organic Chemistry, Ellis Horwood Limited Chichester, 1984).

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1 Compound of Formula II, wherein A is OH, B is G and W TakenTogether

V is CH₃, L is CH₂CH₃, T is —CH₂(C═CH₂)CH₂—, and Q is

Step 1: Compound of formula II wherein A and B taken together with thecarbon atom to which they are attached are C═NOAc, G is OH, W is H, V isCH₃, L is CH₂CH₃, T is —CH₂(C═CH₂)CH₂—, and Q is

Step 1a.

To a flask containing a solution of commercially available Ery A oxime(1 eq.) in MeOH was slowly bubbled in anhydrous HCl gas (3.1 eq.) at 20to 30° C. for 2 hrs. After HCl gas bubbling stops, the reaction mixturewas stirred for 1 hr at room temperature. The mixture was thenconcentrated to about half the volume, and then quenched with dilute HClsolution. The resulting solution was extracted 4 times withdichloromethane. The aqueous solution was then basified with aqueouspotassium carbonate solution until pH 9.5 to 10. The mixture wasextracted 4 times with dichloromethane. The combine organic extractswere washed once with water, and then evaporated to dryness. The productwas carried directly for the next step without further purification.

MS (ESI): m/z=591 [M+H].

Step 1b.

A solution of the compound from step (1a) in THF (12 L) was concentratedto a remaining volume about 9 L to azeotropically dry the materialbefore acetylation reaction. To this clear THF solution was chargedtriethylamine (3.0 eq.), and then slowly charged Ac₂O (2.3 eq.) at20-30° C. over the period of about 30 min. Upon the completion of theaddition, the reaction mixture was agitated at 25° C. for additional 3hours. The reaction was diluted with EtOAc, subsequently washed 4 timeswith saturated aqueous NaHCO₃ solution, and 4 times with water. Theorganic solution was evaporated to dryness to afford the desired crudeproduct which was purified by crystallization with EtOAc/Hex.

MS (ESI): m/z=675 [M+H].

Step 1c.

To a cloudy solution of compound from step (1b) in tolulene was addedcarbonic acid 2-tert-butoxycarbonyloxymethyl-allyl ester tert-butylester (1.6 eq.) (prepared according to patent WO 03/097659 A1). Theresulting mixture was degassed 3 times at 33° C. before Pd₂(dba)₃ (4 mol%) and dppb (8 mol %) were added and the resulting mixture was heated toreflux for 5 hours. After this time, the reaction was cooled back toroom temperature and was concentrated under vacuo. The residue waspassed through a short silica gel column eluting with 100% EtOAc to 95:5(EtOAc:acetone) to give and the eluted product was concentrated andcrystallized out from EtOAc to give the desired target.

MS (ESI): m/z 627.37 [M+H].

¹³C NMR (CDCl₃, ppm) δ: 176.8, 171.3, 170.2, 168.0, 143.0, 118.9, 102.3,81.0, 80.0, 77.6, 75.0, 74.4, 72.3, 71.9, 70.6, 69.2, 63.55, 63.47,60.6, 43.6, 42.7, 40.9, 37.9, 34.9, 31.0, 28.5, 22.9, 22.1, 21.6, 21.3,21.2, 20.0, 18.9, 16.9, 15.1, 14.4, 12.2, 10.6, 10.5.

Step 2: Compound of formula II, wherein A and B taken together with thecarbon atom to which they are attached are C═O, G is OH, W is H, V isCH₃, L is CH₂CH₃T is —CH₂(C═CH₂)CH₂—, and Q is

To a stirred solution of compound from Example 6 (22 mmol) in ethanolwas slowly added water (75 ml). To this mixture was added NaNO₂ (5 eq.)in one portion and then it was slowly treated with 1N aqueous HCl (110ml). The reaction temperature was warmed to 70° C. over 20 min and wasallowed to stir at this temperature for 2 hours. After the solution wascooled back to room temperature, it was basified with saturated NaHCO₃to a pH of 9-10 and then extracted 5 times with dichloromethane. Thecombined organic extracts were washed once with brine, dried over MgSO₄,filtered and concentrated. The residue was purified by crystallizationto afford the desired product.

MS (ESI): m/z 628.09 [M+H].

¹³C NMR (CDCl₃, ppm) δ: 220.6, 177.0, 143.9, 118.3, 104.5, 81.4, 80.7,75.3, 75.1, 72.6, 70.8, 69.70, 69.66, 66.0, 63.7, 45.2, 43.7, 42.7,40.5, 38.8, 38.5, 28.6, 22.7, 22.2, 21.4, 18.8, 16.6, 12.3, 12.1, 10.9,10.6.

Step 3: Compound of formula II wherein A and B taken together with thecarbon atom to which they are attached are C═O, G is OH, W is H, V isCH₃, L is CH₂CH₃, T is —CH₂(C═CH₂)CH₂—, and Q is

To a solution of compound from Example 2 in CH₂Cl₂ was added Ac₂O (1.2eq.). The resulting solution was stirred at room temperature for 2.5hours before it was diluted with EtOAc, washed 2 times with saturatedNaHCO₃, once with brine, dried over MgSO₄ and concentrated under vacuumto give a white solid.

MS (ESI): m/z 670.10 [M+H].

¹³C NMR (CDCl₃, ppm) δ: 220.6, 176.9, 170.1, 143.8, 118.3, 102.4, 80.8,80.5, 75.3, 75.1, 72.6, 72.0, 69.7, 69.3, 63.8, 63.5, 45.0, 43.6, 42.7,40.9, 38.7, 38.4, 30.9, 22.8, 22.2, 21.6, 21.2, 18.7, 16.9, 12.2, 12.1,10.7, 10.6.

Step 4. Compound of formula II, wherein A and B taken together with thecarbon atom to which they are attached are C═O, G and W taken togetheris

V is CH₃, L is CH₂CH₃, T is —CH₂(C═CH₂)CH₂—, and Q is

To a mixture of compound from example 3 (1.54 mmol), CDI (4.0 eq.), inTHF (25 ml), and DMF (5 ml) was added NaHMDS (1.5 eq.) dropwise undernitrogen at room temperature. The resulting solution was further stirredat room temperature overnight. The yellow suspension was cannulated to avessel containing 5 ml of liquid ammonia. The resulting mixture wassealed and stirred at room temperature overnight. The mixture was thenpoured into a mixture of EtOAc (200 ml) and 5% NaH₂PO₄ (150 ml). Theaqueous layer was extracted with EtOAc and the combined organic layerswere washed twice with 5% NaH₂PO₄, once with saturated NaHCO₃, driedover Na₂SO₄, filtered and concentrated under vacuum to yield anoff-white foam (92% yield).

MS (ESI): m/z 695.25 [M+H].

¹³C NMR (CDCl₃, ppm) δ: 218.1, 177.1, 170.1, 158.5, 144.0, 119.3, 102.2,85.0, 80.7, 80.1, 74.3, 72.6, 71.9, 69.3, 63.4, 63.3, 60.6, 58.2, 45.2,43.5, 42.5, 40.8, 38.7, 38.2, 30.9, 23.5, 22.2, 21.6, 21.3, 21.2, 18.9,14.4, 14.1, 14.0, 11.8, 10.8, 10.2 ppm.

Step 5: A solution of step 4 (694 mg, 1.0 mmol) in anhydrous THF (10 mL)was treated with a solution of lithium trimethylsilylacetylide in THF(0.5 M, 20 mL, 10 mmol) over 5 minutes at 0° C. under nitrogen. Afterthe addition was complete, the reaction mixture was allowed to warm 25°C., and stirred for 6.5 hours. The reaction mixture was treated withsaturated aqueous NH₄Cl. The volatile was evaporated off and the residueis partitioned (ethyl acetate and 5% aqueous K₂CO₃). The organics werewashed with water and brine, dried (Na₂SO₄) and evaporated to give thetitled compound. The crude product was used directly for next step.

ESIMS m/z=751.49 (M+H)⁺.

Example 2 Compound of Formula II, wherein A is OH, B is G and W TakenTogether is

V is CH₃, L is CH₂CH₃, T is —CH₂(C═CH₂)CH₂—, and Q is

A solution of the crude compound from Example 1 step 5 (1.0 mmol atmost) in MeOH (40 mL) was treated with K₂CO₃ (1.025 g, 7.4 mmol) at roomtemperature for 14 hours before evaporation. The residue was partitioned(ethyl acetate and water), washed (water and brine), dried (Na₂SO₄).Evaporation gave the titled compound (715 mg).

ESIMS m/z=679.52 (M+H)⁺.

Example 3 Compound of Formula II wherein A is OH, B is G and W TakenTogether is

V is CH₃, L is CH₂CH₃, T is —CH₂(C═CH₂)CH₂— and Q is

The crude compound from step xx (1.0 mmol at most) was treated withacetic anhydride (3.0 mL) in CH₂Cl₂ (30 mL) at room temperature for 2.5hours. It was evaporated and the residue was re-dissolved in toluene andre-evaporated. The residue was chromatographed (silica, hexane-acetone)to give the title compound (80.4% yield).

ESIMS m/z=721.49 (M+H)⁺.

¹³C (CDCl₃) 177.1, 171.4, 170.2, 157.8, 145.4, 112.1, 103.2, 84.3, 80.3,80.2, 78.1, 74.2, 74.0, 69.3, 64.4, 63.6, 58.1, 45.4, 43.8, 40.8, 40.3,37.1, 36.0, 31.0, 22.6, 21.7, 21.2, 14.4, 14.2, 12.9, 10.9, 10.8.

Example 4 Compound of Formula II wherein A is OH, B is CH═CH₂, G and WTaken Together is

V is CH₃, L is CH₂CH₃, T is —CH₂(C═CH₂)CH₂—, and Q is

A solution of compound from Example 3 (100 mg, 0.14 mmol) in ethylacetate (10 mL) and 1-hexene (2.0 mL, 16 mmol) was hydrogenated with ahydrogen balloon in the presence of Lindlar's catalyst (5% Pd on CaCO₃poisoned with lead, 59 mg, 0.028 mmol) at room temperature for 3 hours.The reaction mixture was filtered through Celite, and concentrated invacuo to give the titled compound (100 mg, 100%).

ESIMS m/z=723.51 (M+H)⁺.

Example 5 Compound of Formula VII, wherein X₂ is CH₂Y₂n is O, Z₂ and R₂₀are Hydrogen and R_(p) is Ac

A solution of compound from Example 4 (284 mg, 0.39 mmol) intrifluoroacetic acid (5.5 mL) was stirred at 0° C. for 1 hour and thenat room temperature for 4.5 hours before being evaporated. The residuewas partitioned (EtOAc/saturated aqueous sodium bicarbonate). Theorganic was washed with water and brine, dried (Na₂SO₄) and evaporatedto give a crude intermediate. It was then dissolved in MeOH (5 mL) andstood at room temperature for 40 minutes before evaporation to give acrude mixture (265 mg). It was finally treated with acetic anhydride(0.5 mL) in CH₂Cl₂ at room temperature for 5 hours before beingevaporated. The residue was re-dissolved in toluene and re-evaporated togive the crude title compound (294 mg).

ESIMS m/z=723.50 (M+H)⁺.

Example 6 Compound of Formula VII wherein X₂ is CH₂, Y₂ is O(CO)NH, Z₂is CH₂Ph, R₂₀ are Hydrogen and R_(P) is Ac

A solution of compound from Example 5 (0.14 mmol at most) indichloromethane (5 mL) was treated with benzyl isocyanate (0.10 mL, 0.81mmol) in the presence of triethylamine (0.5 mL, 3.59 mmol) at roomtemperature for 14 hours. It was evaporated and the residue wasdissolved in acetonitrile and water (5:1, 6 mL) and further purified byHPLC to afford the titled compound (5.6 mg).

ESIMS m/z=856.56 (M+H)⁺.

Example 7 Compound of Formula VII, wherein X₂ is CH₂, Y₂ is O(CO)NH, Z₂is CH₂Ph, R₂₀ are Hydrogen and R_(p) is H

A solution of compound from Example 6 in methanol is stirred at roomtemperature for 5 h. The organic solution is concentrated in vacuo.Purification by HPLC affords the titled compound.

The same starting material from Example 5 is used in the preparation of174-346 listed in Table 2 using the similar method delineated inExamples 6 and 7 for compound to prepare each of the compounds listed inTable 2.

In all of the following examples a mixture of stereoisomers are presentwhich may be separated by flash chromatography, crystallization or HPLC.

The substituted amines used in the following examples are eithercommercially available or can be made according to published procedures.

1. Compounds represented by formula (I) or (II):

or the racemates, enantiomers, diastereomers, geometric isomers,tautomers, solvates, pharmaceutically acceptable salts and estersthereof, wherein T is (a) —R₁—, where R₁ is substituted or unsubstituted—C₁-C₈ alkylene-, —C₂-C₈ alkenylene or —C₂-C₈ alkynylene, containing 0,1, 2, or 3 heteroatoms selected from O, S or N; (b) —R₁—(C═O)—R₂—, whereR₂ is independently selected from R₁; (c) —R₁—(C═N—E—R₃)—R₂—, where E isabsent, O, OC(O), NH, NHC(O), NHC(O)NH or NHSO₂; and R₃ is independentlyselected from the group consisting of: (1) hydrogen; (2) aryl;substituted aryl; heteroaryl; substituted heteroaryl; and (3) R₄, whereR₄ is substituted or unsubstituted —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or—C₂-C₈ alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, Sor N; and (4) substituted or unsubstituted, saturated or unsaturatedC₃-C₁₂ cycloalkyl; (d) —R₁—[C(OR₅)(OR₆)]—R₂—, where R₅ and R₆ areselected from the group consisting of C₁-C₁₂ alkyl, aryl or substitutedaryl; or taken together is —(CRxRy)_(m)—, where m is 2 or 3, Rx and Ryare independently selected from hydrogen and R₄; (e)—R₁—[C(SR₅)(SR₆)]—R₂—; or (f) —R₁—(C═CH—R₃)—R₂—; one of A and B is R_(a)and the other is OR_(a), wherein R_(a) is independently selected from:(a) hydrogen; and (b) —R₄; alternatively, A and B taken together withthe carbon atom to which they are attached to form ═CHCH(R_(b))X₁ or═CHM₁C(R_(b))═N—OR_(c), wherein R_(b) is selected from the groupconsisting of: (a) hydrogen; (b) —R₃; (c) —C(O)—R_(d), wherein R_(d) isindependently selected from halogen and R₃; (d) —C(O)—O—R_(d); and (e)—C(O)—NR₈R₉ wherein R₈ and R₉ are each independently selected R₃;alternatively, R₈ and R₉ taken together with the nitrogen atom to whichthey are connected form a 3- to 7-membered ring which may optionallycontain one or more heterofunctions selected from the group consistingof: —O—, —NH—, —N(R₄)—, —N(R₁₀)—, —S(O)_(n)—, wherein n=0, 1 or 2, andR₁₀ is selected from aryl; substituted aryl; heteroaryl; and substitutedheteroaryl; Rc is selected from the group consisting of: (a) hydrogen;(b) —R₄; (c) —R₁₀; (d) —(CO)R₃; (e) —(CO)NHR₃; (f) —(CO)OR₃; (g)—C(O)—NR₈R₉; and (h) —C(O)—NR₁₁NR₁₂R₁₃; wherein R₁₁ is hydrogen oralkyl, and R₁₂ and R₁₃ are independently selected from R₄; X₁ isselected from the group consisting of: (a) hydrogen; (b) oxo; (c) azido;(d) cyano; (e) —R₄; (f) —R₁₀; (g) —(CO)R₃; (h) —(CO)NHR₃; (i) —(CO)OR₃;(j) —C(O)—NR₈R₉; (k) —OR₁₄, where R₁₄ is selected from the groupconsisting of N-phthalimido and Rc; (l) —SR₃; (m) —NR₈R₉; and (n)—NR₃R₁₄; M₁ is absent or R₁; L is independently selected from R₄; W isselected from: (a) hydrogen; (b) —R₄; (c) —C(O)R₃; (d) —C(O)O—R₃; and(e) —C(O)N(R₈R₉); Q is: (a) —R₃; (b) —(CO)R₃; (c) —(CO)NHR₃; (d)—(CO)OR₃; (e) —(SO)₂R₃; (f) monosaccharide; (g) disaccharide; or (h)trisaccharide; Z is: (a) hydrogen; (b) —N₃; (c) —CN; (d) —NO₂; (e)—CONH₂; (f) —COOH; (g) —CHO; (h) —R₄; (i) —COOR₄; (j) —C(O)R₄; or (k)—C(O)NR₈R₉; when U is hydrogen, V is selected from the group consistingof: (a) hydrogen; (b) —OR₃; (c) —OC(O)R₃; (d) —OC(O)NHR₃; (e) —OS(O)₂R₃;(f) —O-monosaccharide; and (g) —O-disaccharide; alternatively, U and Vtaken together with is oxo; each of X and Y is independently: a)hydrogen; b) hydroxy; c) halogen; or d) —R₄; G is selected from thegroup consisting of: a) hydrogen; b) hydroxy; c) —O—R₄; d) —O—R₁₀;alternatively, G and W taken together to a form cyclic structureselected from:

 where M is O or N—J—R₂₀, and where J is absent, O, NH, NH(CO), or N═CH;and R₂₀ is selected from the group consisting of: i. hydrogen; ii. R₄;and iii. R₁₀.
 2. A compound according to claim 1 represented by formula(III):

where X₂ is C(O) or CH₂; Y₂ is absent, O, S, NH, CO, (CO)O, (CO)NH, SO,SO₂, CS, (CS)NH, O(CO)O, O(CO)NH, O(CO), (CO)O, NH(CO)O, NH(CO),NH(CO)NH, NH(SO₂), SO₂NH, NH(SO₂)NH, or C═N—E—R₃; Z₂ is hydrogen, R₄ orR₁₀; R_(p) is hydrogen, hydroxy protecting group, ester or hydroxyprodrug; and E, R₃, R₄, R₁₀, Y and T are as previously defined inclaim
 1. 3. A compound according to claim 1 represented by formula(III):

where X₂ is C(O) or CH₂, Y₂ is absent, O, S, NH, CO, (CO)O, (CO)NH, SO,SO₂, CS, (CS)NH, O(CO)O, O(CO)NH, O(CO), (CO)O, NH(CO)O, NH(CO),NH(CO)NH, NH(SO₂), SO₂NH, NH(SO₂)NH, or C═N-E-R₃, Z₂ is hydrogen, R₄ orR₁₀, R_(p) is hydrogen, hydroxy protecting group, ester or hydroxyprodrug; and E, R₃, R₄, R₁₀, and Y are as previously defined in claim 1.4. A compound according to claim 1 represented by formula (V):

where X₂ is C(O) or CH₂, Y₂ is absent, O, S, NH, CO, (CO)O, (CO)NH, SO,SO₂, CS, (CS)NH, O(CO)O, O(CO)NH, O(CO), (CO)O, NH(CO)O, NH(CO),NH(CO)NH, NH(SO₂), SO₂NH, NH(SO₂)NH, or C═N-E-R₃, Z₂ is hydrogen, R₄ orR₁₀, R_(p) is hydrogen, hydroxy protecting group, ester or hydroxyprodrug; and E, R₃, R₄, R₁₀, and Y are as previously defined in claim 1.5. A compound according to claim 1 represented by formula (VI):

where X₂ is C(O) or CH₂, Y₂ is absent, O, S, NH, CO, (CO)O, (CO)NH, SO,SO₂, CS, (CS)NH, O(CO)O, O(CO)NH, O(CO), (CO)O, NH(CO)O, NH(CO),NH(CO)NH, NH(SO₂), SO₂NH, NH(SO₂)NH, or C═N-E-R₃, Z₂ is hydrogen, R₄ orR₁₀, R_(p) is hydrogen, hydroxy protecting group, ester or hydroxyprodrug; and E, R₃, R₄, R₁₀, T, and R₂₀ are as previously defined inclaim
 1. 6. A compound according to claim 1 represented by formula(VII):

where X₂ is C(O) or CH₂, Y₂ is absent, O, S, NH, CO, (CO)O, (CO)NH, SO,SO₂, CS, (CS)NH, O(CO)O, O(CO)NH, O(CO), (CO)O, NH(CO)O, NH(CO),NH(CO)NH, NH(SO₂), SO₂NH, NH(SO₂)NH, or C═N-E-R₃, Z₂ is hydrogen, R₄ orR₁₀, R_(p) is hydrogen, hydroxy protecting group, ester or hydroxyprodrug; and E, R₃, R₄, R₁₀, and R₂₀ are as previously defined inclaim
 1. 7. A compound according to claim 1 represented by formula(VIII):

where X₂ is C(O) or CH₂, Y₂ is absent, O, S, NH, CO, (CO)O, (CO)NH, SO,SO₂, CS, (CS)NH, O(CO)O, O(CO)NH, O(CO), (CO)O, NH(CO)O, NH(CO),NH(CO)NH, NH(SO₂), SO₂NH, NH(SO₂)NH, or C═N-E-R₃, Z₂ is hydrogen, R₄ orR₁₀, R_(p) is hydrogen, hydroxy protecting group, ester or hydroxyprodrug; and E, R₃, R₄, R₁₀, and R₂₀ are as previously defined inclaim
 1. 8. A compound of claim 1 having the Formula A, selected fromcompounds 1-173 of Table 1:

wherein Z₂ is delineated for each example in Table 1 TABLE 1 CompoundNo. —Z₂  (1)

 (2)

 (3)

 (4)

 (5)

 (6)

 (7)

 (8)

 (9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

(48)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

(62)

(63)

(64)

(65)

(66)

(67)

(68)

(69)

(70)

(71)

(72)

(73)

(74)

(75)

(76)

(77)

(78)

(79)

(80)

(81)

(82)

(83)

(84)

(85)

(86)

(87)

(88)

(89)

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

(98)

(99)

(100) 

(101) 

(102) 

(103) 

(104) 

(105) 

(106) 

(107) 

(108) 

(109) 

(110) 

(111) 

(112) 

(113) 

(114) 

(115) 

(116) 

(117) 

(118) 

(119) 

(120) 

(121) 

(122) 

(123) 

(124) 

(125) 

(126) 

(127) 

(128) 

(129) 

(130) 

(131) 

(132) 

(133) 

(134) 

(135) 

(136) 

(137) 

(138) 

(139) 

(140) 

(141) 

(142) 

(143) 

(144) 

(145) 

(146) 

(147) 

(148) 

(149) 

(150) 

(151) 

(152) 

(153) 

(154) 

(155) 

(156) 

(157) 

(158) 

(159) 

(160) 

(161) 

(162) 

(163) 

(164) 

(165) 

(166) 

(167) 

(168) 

(169) 

(170) 

(171) 

(172) 

(173) 


9. A compound of claim 1 having the Formula B, selected from compounds174-346 of Table 2:

wherein Z₂ is delineated for each example in Table 2 TABLE 2 CompoundNo. —Z₂ (174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)

(201)

(202)

(203)

(204)

(205)

(206)

(207)

(208)

(209)

(210)

(211)

(212)

(213)

(214)

(215)

(216)

(217)

(218)

(219)

(220)

(221)

(222)

(223)

(224)

(225)

(226)

(227)

(228)

(229)

(230)

(231)

(232)

(233)

(234)

(235)

(236)

(237)

(238)

(239)

(240)

(241)

(242)

(243)

(244)

(245)

(246)

(247)

(248)

(249)

(250)

(251)

(252)

(253)

(254)

(255)

(256)

(257)

(258)

(259)

(260)

(261)

(262)

(263)

(264)

(265)

(266)

(267)

(268)

(269)

(270)

(271)

(272)

(273)

(274)

(275)

(276)

(277)

(278)

(279)

(280)

(281)

(282)

(283)

(284)

(285)

(286)

(287)

(288)

(289)

(290)

(291)

(292)

(293)

(294)

(295)

(296)

(297)

(298)

(299)

(300)

(301)

(302)

(303)

(304)

(305)

(306)

(307)

(308)

(309)

(310)

(311)

(312)

(313)

(314)

(315)

(316)

(317)

(318)

(319)

(320)

(321)

(322)

(323)

(324)

(325)

(326)

(327)

(328)

(329)

(330)

(331)

(332)

(333)

(334)

(335)

(336)

(337)

(338)

(339)

(340)

(341)

(342)

(343)

(344)

(345)

(346)


10. A compound of claim 1 having the Formula C, selected from compounds347-370 of Table 3:

wherein Y₂, Z₂, T, and R_(p) are delineated for each example in Table 3TABLE 3 Compound No. T Y₂ Z₂ R_(p) (347) —CH₂(C═CH₂)CH₂— —O(C═O)NHNH—

Ac (348) —CH₂(C═CH₂)CH₂— —O(C═O)NHNH—

H (349) —CH₂(C═O)CH₂— —O(C═O)NHNH—

H (350) —CH₂(C═CH₂)CH₂— —NH—

H (351) —CH₂(C═CH₂)CH₂— —NH—

Ac (352) —CH₂(C═CH₂)CH₂— —NH—

H (353) —CH₂(C═CH₂)CH₂— —NH—

Ac (354) —CH₂(C═CH₂)CH₂— —NH—

H (355) —CH₂(C═CH₂)CH₂— —NH—

Ac (356) —CH₂(C═CH₂)CH₂— —NH—

H (357) —CH₂CH═CHCH₂— —NH—

H (358) —CH₂(C═CH₂)CH₂— —NH—

Ac (359) —CH₂(C═CH₂)CH₂— —NH—

H (360) —CH₂(C═CH₂)CH₂— —NH—

H (361) —CH₂(C═CH₂)CH₂— —NH—

H (362) —CH₂(C═CH₂)CH₂— —NH(C═O)NH—

Ac (363) —CH₂(C═CH₂)CH₂— —NH(C═O)NH—

H (364) —CH₂(C═CH₂)CH₂— —NH(C═O)NH—

H (365) —CH₂(C═CH₂)CH₂— —NH(C═O)O—

H (366) —CH₂(C═CH₂)CH₂— —NH(C═O)NH—

Ac (367) —CH₂(C═CH₂)CH₂— —NH(C═O)NH—

H (368) —CH₂CH═CHCH₂— —NH(C═O)NH—

H (369) —CH₂CH═CHCH₂— —NH—

H (370) —CH₂CH═CHCH₂— —NH—

H.


11. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable salt,ester or prodrug thereof, in combination with a pharmaceuticallyacceptable carrier.
 12. A method for treating a bacterial infection in asubject, comprising administering to said subject a therapeuticallyeffective amount of a pharmaceutical composition according to claim 11.13. A method of treating cystic fibrosis in subject, comprisingadministering to said subject, a therapeutically effective amount of apharmaceutical composition of claim
 11. 14. A method of treatinginflammation in a subject comprising administering to said subject,therapeutically effective amount of a pharmaceutical composition ofclaim 11.